The objective of this proposal is to understand the neural and molecular mechanisms of memory consolidation, the process by which an initially labile memory becomes progressively more stable with time. Recently, we identified three genes whose expression is modulated during the consolidation phase of long- term facilitation (LTF), a neural mechanism underlying a simple form of long-term memory (LTM) termed long-term sensitization (LTS). These genes are creb1, creb2 and synapsin. Our preliminary data suggest that the regulation of these genes contributes to consolidation. For example, blocking CREB1 1 h after treatment with serotonin (5-HT), a transmitter that mediates sensitization, blocked LTF. We will examine the significance of changes in the expression of creb1, creb2 and synapsin in the consolidation of LTF, and we will test the hypothesis that changes in the expression of synapsin are critical for the formation of new synapses during consolidation. The following aims will examine the significance of changes in the expression of these genes in the consolidation of LTF. The first aim is to examine the dynamics of CREB1, CREB2, and synapsin protein and mRNA and the dynamics of CREB phosphorylation and of CRE-dependent transcription following sensitization training or treatment with serotonin (5-HT). The second aim is to investigate the functional significance of the increased expression of CREB1 mRNA and protein for LTF consolidation. The third aim is to investigate the functional significance of changes in CREB2 mRNA and protein for LTF consolidation. The fourth aim is to investigate the functional significance of changes in synapsin expression for LTF consolidation. The fifth aim is to investigate the behavioral significance of the complex pattern of changes in CREB1 and CREB2 expression for LTS. Elucidating how changes in the expression of CREB1, CREB2, and synapsin affect consolidation is crucial for developing a model describing the sequence and duration of the biochemical steps involved in LTF, and the consequent formation of LTM. In many model systems, creb and synapsin appear necessary for at least some forms of long-term synaptic strengthening (e.g., late LTP) and for LTM. Therefore, we predict that a unified model describing the dynamic expression of, and requirement for, creb1, creb2 and synapsin in neural plasticity and learning will significantly enhance understanding of the mechanisms underlying human memory and provide a rationale for improving memory in those afflicted by memory disorders. PUBLIC HEALTH RELEVANCE This proposal seeks to characterize the time courses of expression of three genes (creb1, creb2, and synapsin) implicated in the establishment of long-term synaptic changes, which contribute to memory. In addition, the proposal seeks to characterize the extent and duration of the requirement for these genes in the consolidation of memory. Knowledge of the sequence and duration of gene expression underlying long-term synaptic changes will significantly enhance our understanding of learning and memory in humans, and will help development of treatment for neurological disorders that affect learning and memory.